Post-lumpectomy intracavitary retention and lymph node targeting of (99m)Tc-encapsulated liposomes in nude rats with breast cancer xenograft.

Liposomes are recognized drug delivery systems with tumor-targeting capability. In addition, therapeutic or diagnostic radionuclides can be efficiently loaded into liposomes. This study investigated the feasibility of utilizing radiotherapeutic liposomes as a new post-lumpectomy radiotherapy for early-stage breast cancer by determining the locoregional retention and systemic distribution of liposomes radiolabeled with technetium-99m ((99m)Tc) in an orthotopic MDA-MB-231 breast cancer xenograft nude rat model. To test this new brachytherapy approach, a positive surgical margin lumpectomy model was set up by surgically removing the xenograft and deliberately leaving a small tumor remnant in the surgical cavity. Neutral, anionic, and cationic surface-charged fluorescent liposomes of 100 and 400 nm diameter were manufactured and labeled with (99m)Tc-BMEDA. Locoregional retention and systemic distribution of (99m)Tc-liposomes injected into the post-lumpectomy cavity were determined using non-invasive nuclear imaging, ex vivo tissue gamma counting and fluorescent stereomicroscopic imaging. The results indicated that (99)Tc-liposomes were effectively retained in the surgical cavity (average retention was 55.7 ± 24.2% of injected dose for all rats at 44 h post-injection) and also accumulated in the tumor remnant (66.9 ± 100.4%/g for all rats). The majority of cleared (99m)Tc was metabolized quickly and excreted into feces and urine, exerting low radiation burden on vital organs. In certain animals (99m)Tc-liposomes significantly accumulated in the peripheral lymph nodes, especially 100 nm liposomes with anionic surface charge. The results suggest that post-lumpectomy intracavitary administration of therapeutic radionuclides delivered by 100-nm anionic liposome carrier is a potential therapy for the simultaneous treatment of the surgical cavity and the draining lymph nodes of early-stage breast cancer.

Postlumpectomy focal brachytherapy for simultaneous treatment of surgical cavity and draining lymph nodes.

PURPOSE: The primary objective was to investigate a novel focal brachytherapy technique using lipid nanoparticle (liposome)-carried ß-emitting radionuclides (rhenium-186 [(186)Re]/rhenium-188 [(188)Re]) to simultaneously treat the postlumpectomy surgical cavity and draining lymph nodes. METHODS AND MATERIALS: Cumulative activity distributions in the lumpectomy cavity and lymph nodes were extrapolated from small animal imaging and human lymphoscintigraphy data. Absorbed dose calculations were performed for lumpectomy cavities with spherical and ellipsoidal shapes and lymph nodes within human subjects by use of the dose point kernel convolution method. RESULTS: Dose calculations showed that therapeutic dose levels within the lumpectomy cavity wall can cover 2- and 5-mm depths for (186)Re and (188)Re liposomes, respectively. The absorbed doses at 1 cm sharply decreased to only 1.3% to 3.7% of the doses at 2 mm for (186)Re liposomes and 5 mm for (188)Re liposomes. Concurrently, the draining sentinel lymph nodes would receive a high focal therapeutic absorbed dose, whereas the average dose to 1 cm of surrounding tissue received less than 1% of that within the nodes. CONCLUSIONS: Focal brachytherapy by use of (186)Re/(188)Re liposomes was theoretically shown to be capable of simultaneously treating the lumpectomy cavity wall and draining sentinel lymph nodes with high absorbed doses while significantly lowering dose to surrounding healthy tissue. In turn, this allows for dose escalation to regions of higher probability of containing residual tumor cells after lumpectomy while reducing normal tissue complications.

Radiobiological characterization of post-lumpectomy focal brachytherapy with lipid nanoparticle-carried radionuclides.

Post-operative radiotherapy has commonly been used for early stage breast cancer to treat residual disease. The primary objective of this work was to characterize, through dosimetric and radiobiological modeling, a novel focal brachytherapy technique which uses direct intracavitary infusion of ß-emitting radionuclides (186Re/188Re) carried by lipid nanoparticles (liposomes). Absorbed dose calculations were performed for a spherical lumpectomy cavity with a uniformly injected activity distribution using a dose point kernel convolution technique. Radiobiological indices were used to relate predicted therapy outcome and normal tissue complication of this technique with equivalent external beam radiotherapy treatment regimens. Modeled stromal damage was used as a measure of the inhibition of the stimulatory effect on tumor growth driven by the wound healing response. A sample treatment plan delivering 50 Gy at a therapeutic range of 2.0 mm for 186Re-liposomes and 5.0 mm for 188Re-liposomes takes advantage of the dose delivery characteristics of the ß-emissions, providing significant EUD (58.2 Gy and 72.5 Gy for 186Re and 188Re, respectively) with a minimal NTCP (0.046%) of the healthy ipsilateral breast. Modeling of kidney BED and ipsilateral breast NTCP showed that large injected activity concentrations of both radionuclides could be safely administered without significant complications.